Obesity is one of the major public health problems of the 21st century with significant consequences on health of the individuals and impact on the national economies. The most common cause of obesity is diet-induced, i.e., consumption of more calories than one can metabolize. In view of the rapidly growing number of obese people throughout the world, the global market for anti-obesity drugs is estimated to reach $3.4 billion by 2016. However, currently available drugs for the treatment of obesity have significant limitations in terms of safety, efficacy or both. Thus, there is a high unmet need for safe and efficacious medications for the prevention or treatment of obesity. This invention discloses a potential drug target for the treatment of diet-induced overweight or obesity. This approach involves increasing the metabolism of consumed excess calories, which may prove to be safer or tolerable than the other two approaches, namely suppression of the appetite or interfering with the absorption of fat in the intestines. It is possible to develop orally effective chemical compounds that selectively act at the disclosed target as potential anti-obesity drugs.
According to the World Health Organization, a Body Mass Index (BMI)>25 is overweight, and a BMI>30 is obesity. Overweight and obesity are no more the problems of high-income countries of the world. They are rapidly rising in low- and middle-income countries.
In 2008 the World Health Organization estimated that globally more than 1.4 billion adults were overweight; and the 2010 estimates showed that more than 40 million children under five years are overweight. Overweight and obesity are the fifth leading risk for global deaths, accounting for 2.8 million deaths each year. In fact, overweight and obesity are linked to more deaths worldwide than underweight.
Raised BMI is a major risk factor for cardiovascular and musculoskeletal disorders, and certain types of cancers, such as breast and colon cancers. In fact, 44% of the diabetic burden, 23% of the ischemic heart disease burden and between 7% and 14% of certain cancer burdens are attributable to overweight and obesity.
The global economic burden of overweight and obesity are not well established. But the numbers are more accurately available for the United States. Over the past 50 years the prevalence of obesity in the USA has almost tripled from 13% to 34%, with the percentage of Americans who are extremely or “morbidly” obese rising from 0.9 to 6. The estimated annual medical costs due to obesity are about $190 billion. The indirect costs due to overweight and obesity are also sky rocketing. For example, it is estimated that airlines incur about $5 billion annually for additional jet fuel needed to fly obese or heavier people as compared to the fuel needed to fly the same number of people based on the body weights prevalent in 1960s. Automobiles also consume extra gasoline amounting to about $4 billion to transport heavier people in the USA. The annual costs due to absenteeism among over weight and obese people are also very high. In fact, according to a study, the costs of obesity exceed those of smoking.
According to the World Health Organization, the fundamental cause of obesity and overweight is energy imbalance between calories consumed and calories expended. In recent decades globally there has been an increase in caloric intake and a decrease in the physical activity, driving the incidence of obesity high. Although supportive environments and communities resulting in consumption of healthy foods and regular physical activity are the best to prevent overweight and obesity, these do not happen often, in part because of the complex nature of modern day living.
Currently used modalities as well as the pipeline drugs for the prevention and/or treatment of obesity fall into the following three categories: (1) drugs that suppress appetite by acting on the brain (e.g., sibutramine (i.e., Reductil® and/or Meridia®); (2) drugs that boost body's metabolic rate (e.g., cannaboid receptor antagonists and Metformin); and (3) drugs that interfere with the body's ability to absorb specific nutrients in food, such as fat (e.g., Orlistat®, Xenical®, and/or Alli®).
Drugs that suppress the appetite by acting on the brain have severe side effects which are neurological and/or psychological in nature. For example, these drugs carry a risk of high blood pressure, faster heart rate, palpitation, restlessness, agitation, insomnia etc. Due to these limitations, drugs that suppress appetite have been withdrawn from the market by the FDA and approval of newer drugs has been made more stringent. Drugs that increase the body's metabolic rate have their own limitations, such as lack of consistent effect resulting in sustained loss of weight. Drugs that block absorption of dietary fat, cause oily stools (steatorrhea), abdominal pain and flatulence.
In view of the side effects with these therapies, combination therapies that target more than one pathway have been developed. However, these also have severe side effects and limitations, despite their efficacy in short-term treatment. Accordingly, there is a high unmet need for safe and effective medications for the prevention or treatment of overweight and obesity, which is expected to drive the anti-obesity market growth in the future. The invention described herein seeks to meet this need.